Endothelial dysfunction is the earliest manifestation of vascular oxidative damage in patients with type 1 diabetes and is present in adolescents. Unfortunately, most studies that have examined endothelial function in type 1 diabetes have done so in the usual fasting state. It is unknown what effect short-term glucose control and acute glucose level have on these measurements. The primary goals of this proposal are: 1) to determine whether acute normalization of plasma glucose levels improves endothelial function in adolescents with type 1 diabetes and 2) to determine the relationship of glycemic control and blood glucose variability as determined from continuous glucose monitoring to endothelial function in healthy type 1 diabetic adolescents. We will use continuous glucose monitoring and hyperinsulinemic clamp to study these aims in 85 adolescents with type 1 diabetes. Adolescents are specifically being studied because of the large body of evidence that cardiovascular disease in diabetes and other conditions is initiated in pre-adulthood. Endothelial function will be measured in resistance vessels as the increase in forearm blood following upper arm vascular occlusion. Forearm blood flow will be measured using venous occlusion plethysmography. We will also explore several mechanistic biomarkers that potentially contribute to vascular risk in children. Blood samples will be investigated for markers of glycemic control (glucose, HBA1C), inflammation (CRP, IL6), oxidative stress (total antioxidant capacity, serum nitrated protein), endothelial stress (soluble ICAM, e-selectin) and endothelial repair (endothelial progenitor cells) using established assays. Once this information is available it may become possible to develop and validate models for prediction of endothelial dysfunction in type 1 diabetes. Such models will aid in early detection or risk stratification of disease, and will be useful in understanding the biochemical and mechanisms responsible for the early development of diabetic complications. This information will aid in the development of therapeutic agents that could act in the presence of hyperglycemia to prevent, delay or reverse complications. PUBLIC HEALTH RELEVANCE: Good glycemic control clearly prevents diabetic complications and decreases the risk of heart disease in patients with type 1 diabetes. However, it is unclear how acute and short-term variations affect precursor to diabetic complications. For instance there is evidence that wide variations in glucose levels may increase the risks of diabetes. The goal of this study is to examine the effect of glycemic variability and acute normalization on endothelial function in adolescents with type 1 diabetes. The endothelium is the ling of the blood vessels and plays an important role in regulate tissue blood flow. Poor Endothelial function is an early precursor of heart disease and complications in type 1 diabetes. Abnormal endothelial function is present in adolescents with type 1 diabetes before the overt complications. It is therefore important that we learn how it is affected by changes in blood sugar control in this group. We will use continuous glucose monitoring to assess variation in glucose levels over three days and then measure endothelial function before and after acute insulin infusion to bring glucose levels from fasting values to normal levels. We will also examine how glycemic control affects increased inflammation and oxidation in diabetes. These may damage the endothelium. The information these studies yield will give us important knowledge regarding the early causes of heart disease and complications in type 1 diabetes.